CN116997376A

CN116997376A - Method for producing a drug delivery device

Info

Publication number: CN116997376A
Application number: CN202280022039.6A
Authority: CN
Inventors: 法比安·波利
Original assignee: Sensile Medical AG
Current assignee: Sensile Medical AG
Priority date: 2021-03-15
Filing date: 2022-03-08
Publication date: 2023-11-03
Also published as: WO2022194606A1; CA3211671A1; EP4308202A1; EP4059539A1; JP2024509626A

Abstract

A method of producing a drug delivery device comprising-a pre-filled drug container (6), -a fluid package comprising a liquid flow system (7) providing a fluid connection from the drug container to a patient during a drug delivery action of the drug delivery device, -a control unit comprising electronic components, -a housing (2), the method comprising the steps of: a) assembling the components of the fluid package to form the fluid package, b) sterilizing the fluid package, c) providing the pre-filled medicament container, d) assembling the fluid package to the pre-filled medicament container to form a container package system, e) assembling the container package system to the control unit and the housing (2) to form the medicament delivery device, wherein steps c) and d) are performed under aseptic conditions.

Description

Method for producing a drug delivery device

Technical Field

The present invention relates to a method of producing a drug delivery device for subcutaneous administration of a liquid drug. The invention relates in particular to a method of producing a drug delivery device in the form of a patch device.

Background

Drug delivery devices in the form of patch devices for mounting on the skin of a patient for subcutaneous delivery of a liquid drug are known. Some devices typically contain a cartridge or have an internal reservoir filled by the patient/healthcare professional. In this case, a syringe is used to withdraw the drug from the vial and transfer it to the internal reservoir. Since cartridges are common and their handling is very easy, it is advantageous to provide a device that can be used with standard cartridges. The liquid medicament may for example be a biomedical product or other medicament for single injection administration only for a relatively short period of time (depending on the intended use). It is known to provide drug delivery devices in the form of patch devices having single-use disposable components assembled to reusable components containing drive and control electronics, or as a single disposable component.

Reliability, safety, compactness and ease of use of a patient-worn drug delivery device are of great importance. The number of parts and thus the cost of the disposable device is also an important consideration for the disposable components.

In order to meet the safety and reliability requirements, many conventional patch pump drug delivery devices have complex pump mechanisms and are quite bulky. Moreover, long shelf life and adequate sterilization are often difficult to achieve and add to manufacturing costs.

We can consider various methods of manufacturing drug delivery devices. The first method may comprise the steps of:

a) A production fluid bag, a shell and a control unit,

b) Sterilizing the fluid bag, the shell and the control unit,

c) The sterile field is fed into an assembly with a prefilled container.

However, an important issue to consider is that the sterilization process can destroy the electronic components, batteries and medications in the pre-filled container.

Drug delivery devices are typically manufactured by producing their individual components in a first step. After the individual components are produced, the components are sterilized using a sterilization process of known type. After sterilization, the parts are transferred to an area with sterile conditions. In this region, the components are typically assembled. A problem with conventional assembly processes is that these processes are not suitable for including electronic parts, batteries or drug sensitive components in pre-filled containers. Sterilization of electronic components, batteries or sensitive drugs in pre-filled containers may destroy them, a risk that is unacceptable. Therefore, the conventional manufacturing process cannot provide functional assembly, and finally cannot guarantee the safety of the patient.

The second method may comprise the steps of:

a) Manufacturing/installing the fluid bag, the shell and the control unit under aseptic conditions;

b) Assembled with the prefilled container.

An important issue to consider is that this process limits the available manufacturing methods, as welding, bonding, subtractive processes and other processes that produce particles are not suitable under aseptic conditions. This also means that the introduction of many components into the aseptic chamber increases the risk of contaminating the environment of the aseptic chamber.

Because of the inappropriateness of these methods, the current methods generally employ the following:

the drug delivery device is not delivered with the combined pre-filled drug container, which the patient has to place himself. A disadvantage is that this requires more user steps, with the risk of not inserting the medicament container correctly or not closing the lid correctly;

or (b)

The drug container is combined under normal clean room conditions and an ultraviolet light source is added in the area where sterility is required. The ultraviolet light source sterilizes critical portions of the container needle and its septum prior to piercing the barrel needle. The disadvantage of this approach is that it is difficult to show evidence of uv sterilization, as normal clean room conditions may allow for a variety of bacteria, which have yet to be demonstrated for their response to uv light.

Disclosure of Invention

In view of the foregoing, it is an object of the present invention to provide a safe, reliable and compact method of producing a drug delivery device for administering a liquid drug, in the form of a patch device, having a disposable unit, or to be a fully disposable device.

Advantageously, a method of manufacturing a drug delivery device is provided which may be used for administering a liquid drug provided in a drug container having a plunger.

It is advantageous to provide a method of manufacturing a drug delivery device that is easy to use, in particular the number of steps performed by a patient.

Advantageously, a method of producing an economical drug delivery device is provided.

It is therefore important to avoid the need to build expensive production lines in a sterile environment (grade 5 or lower according to the ISO 14644-1 standard).

Advantageously, a method of producing a drug delivery device with a long shelf life is provided.

The object of the present invention has been achieved by providing a method of producing a drug delivery device according to claim 1. The dependent claims set forth various advantageous embodiments.

According to a first aspect of the present invention, there is disclosed herein a method of producing a drug delivery device comprising:

A prefilled drug container, wherein the drug container comprises a barrel portion and a plunger slidably mounted within the barrel portion and sealing the drug within the container,

a fluid package comprising a liquid flow system providing a fluid connection from the drug container to the patient during a drug delivery action of the drug delivery device,

-a control or drive unit comprising electronic components, and

the outer shell is a shell with a hollow,

the method comprises the following steps:

a) Assembling the components of the fluid package to form the fluid package,

b) The fluid-bag is subjected to a sterilization process,

c) Providing a pre-filled medicament container according to the present invention,

d) After sterilization, the fluid package is assembled to a pre-filled drug container to form a container-package system,

e) Assembling the container package system to the control unit and the housing (2) to form a drug delivery device,

wherein steps c) and d) are performed under aseptic conditions.

In an advantageous embodiment, the medicament container comprises a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing medicament within the container,

step a) involves the assembly of a fluid pack of the drug delivery device. The fluid package comprises at least a liquid flow system capable of providing a fluid connection from the pre-filled drug container to the patient's body during a drug delivery action of the drug delivery device. Fluid flow systems typically include different components of different materials. For example, the patient side cannula may comprise metal, while the fluid path is typically constituted by a hose or channel made or formed of plastic parts.

Step b) involves sterilization of the fluid packet. Since the assembled fluid package is not typically manufactured under aseptic conditions, the fluid package must be sterilized to ensure that the patient cannula, barrel needle and overall fluid path are not contaminated. The usual sterilization methods to achieve sterility of the assembly depend on the combination of different materials and the product design (e.g. grooves). Examples of sterilization methods for the fluid Bao Chang include gamma ray, ethylene oxide (ETO) sterilization, nitrogen dioxide (NO 2) sterilization, steam sterilization, vaporized Hydrogen Peroxide (VHP) sterilization, X-ray sterilization, and electron beam sterilization.

Step c) involves providing a prefilled drug container. The container may be made of glass, polymer or other material that is inert to drug stability and preferably biocompatible. Glass is commonly used in FDA approved commercial drug containers produced by many different manufacturers. Thus, aseptic filling and storage of medications in glass containers has been a well established, approved procedure that can expedite the approval process of a drug pump device that protects the medication in the glass container. Polymeric containers, for example made of COP (cyclic olefin polymer) or COC (cyclic olefin copolymer), may be suitable for certain drugs, such as protein drugs, which degrade faster when in contact with glass. After filling, the container is closed with a plunger, typically made of a rubber material. Such containers are filled and closed under aseptic conditions (5 or lower stages as specified in ISO 14644-1).

Step d) involves assembling the fluid pack to the pre-filled drug container to form a container pack system, which may have a fluid connection between the fluid pack and the pre-filled drug container, or may establish the connection separately, e.g. after production or before delivering the drug to the patient.

Step e) involves assembling the container package system to the control or drive unit and the housing to form the drug delivery device. The assembly of the control or drive unit with the user interface of the container package system and the mounting of the housing may be accomplished by standard form fit connections or any other conventional manufacturing method. This may also include welding or gluing processes in order to achieve a watertight or even airtight housing.

Definition of aseptic conditions: in addition to low particle counts, aseptic conditions ensure that the filling and assembly environment is free of pathogens, such as bacteria, viruses and other pathogenic microorganisms. The aseptic conditions may be achieved in a class 5 clean room or a lower class clean room (i.e. a higher standard clean room) as specified in e.g. ISO 14644-1.

In an advantageous embodiment of the method, step e) is not carried out under aseptic conditions. Electronic components are very sensitive to common sterilization methods such as gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization. By performing step e) under non-sterile conditions, damage to the electronic components can be avoided. Thus, there is no risk of any parts being destroyed when assembling the drug delivery device, thereby ensuring patient safety. Thus, the manufacturing method of step e) is not limited to particle-free or low-particle-emission joining techniques.

The container packaging system includes a container housing enclosing a prefilled drug container. The reservoir housing may be connected to a fluid bag so that the sterile state of the prefilled drug container may be simply maintained. The container may be in direct fluid communication with the liquid flow system or the fluid package may include means for connecting the prefilled drug container to the liquid flow system separately (e.g., after manufacture or immediately prior to delivery of the drug to the patient).

The container package system includes a pump system. The pump system is configured to push the plunger further into the pre-filled drug container in order to administer the drug. In an advantageous embodiment, the pump system performs drug delivery by drawing ambient air and injecting it into the reservoir housing.

The pump system comprises a coupling interface of the pump system of the delivery unit, the pump driver providing torque to a rotor of the pumping system, wherein the coupling interface is sealed by a sealing membrane to remain sterile after step b). The seal may be made of a two-component molded thermoplastic elastomer (TPE) or a separate TPE or elastomer that seals against the moving coupling interface. The seal may also be made to completely cover the coupling interface and be broken when the coupling is first rotated. In this case, it may be made of a polyethylene foil (e.g. Tyvek ^TM Foil) instead of an elastic material.

In an advantageous embodiment of the method, the housing comprises a user interface. The user interface may comprise electronic components that are very sensitive to common sterilization methods.

In an advantageous embodiment of the method, the sterilization method of b) is any one of gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization.

In an advantageous embodiment of the method, the assembly step of step e) comprises a form-fitting connection. By performing step e) with a form-fitting connection, the simplicity of this operation may allow it to be performed in the same room (production line) as the filling and closing of the medicament container. The particles and equipment resulting from this step are small in size and thus suitable for aseptic conditions.

In an advantageous embodiment of the method, the form-fit connection provides a gas-tight seal of the prefilled drug container within the container package system. Thus, the prefilled drug container is not only gas-or liquid-tight, but can also be configured to remain sterile in a simple manner throughout the shelf life of the device.

In an embodiment of the method, the herein below described delivery unit without the drug container assembled forms the fluid package, wherein the delivery unit with the drug container assembled forms the container package, and the herein described drive unit forms the control or drive unit comprising electronic components.

In embodiments of the method, the drug delivery device may have any one or more of the additional features of any of the embodiments of the device described herein below.

Also disclosed is a drug delivery device comprising a delivery unit comprising a drug container, a liquid flow system, a pumping system and a housing enclosing at least a part of the drug container, the pumping system and the liquid flow system therein. The medicament container includes a barrel portion and a plunger slidably mounted within the barrel portion and sealing medicament within the container at one end of the barrel portion, the liquid flow system being fluidly connected to the medicament container during delivery of the liquid medicament. The drug container is received within a container receiving cavity of a container housing portion of the housing, the container receiving cavity being fluidly interconnected to a fluid outlet of the pumping system in an airtight manner. The pumping system includes a fluid inlet connected to ambient air, the pumping system being configured to pump ambient air drawn through the fluid inlet into the container receiving cavity, thereby exerting pressure on the rear end of the plunger to deliver the liquid medicament.

In an advantageous embodiment, the pumping system comprises a pump engine comprising:

The stator is a stator which is arranged in a housing,

a rotor rotatably and axially slidably mounted at least partially in the stator, the rotor comprising a first axial extension having a first diameter and a second axial extension having a second diameter larger than the first diameter,

a first valve formed by a first valve seal mounted on the stator about a first axial extension in combination with a first passage in the rotor, the first passage configured to allow fluid communication across the first valve seal when the first valve is in an open position, and

-a second valve formed by a second valve seal mounted on the stator about a second axial extension in combination with a second passage in the rotor, the second passage being configured to allow fluid communication across the second valve seal when the second valve is in the open position.

In an advantageous embodiment, the medicament container is a cartridge.

Also disclosed is a drug delivery device comprising:

-a delivery unit comprising a medicament container comprising a cylindrical portion and a plunger slidably mounted within the cylindrical portion and hermetically sealing an inner surface of the cylindrical portion to contain a liquid medicament within the medicament container; and

-an electronic control system and a plunger sensing system comprising an optical sensor, the optical sensor comprising a transmitter configured to transmit an optical signal to a rear end of the plunger and a receiver configured to receive an optical signal reflected back from the rear end of the plunger, the plunger sensing system being connected to the electronic control system, the electronic control system being configured to measure a time of flight of the optical signal from the transmitter to the receiver and thereby determine a position of the plunger within the cylindrical portion of the medicament container.

In one embodiment, the delivery unit comprises a housing comprising a container housing part comprising a plunger end covering a plunger-facing end of the drug container, the plunger end comprising a transparent sensor window allowing an optical signal to pass through the plunger end of the container housing, the optical sensor being located on or near the sensor window, the transmitter being configured to transmit the optical signal to a rear end of the plunger through the sensor window, the receiver being configured to receive the optical signal reflected from the rear end of the plunger and returned through the sensor window.

In one embodiment, the plunger end of the container housing portion includes a raised portion that positions the sensor window at a distance from the rear end of the plunger end, allowing for optical time-of-flight measurements of the plunger in its initial position.

In one embodiment, the distance from the rear end of the plunger end is in the range of 5mm to 20 mm.

In one embodiment, the delivery unit comprises a housing comprising a container housing part comprising a plunger end covering the end of the drug container facing the plunger, the plunger end comprising a transparent sensor prism allowing an optical signal to pass through the plunger end of the container housing, the optical sensor being positioned on or near a surface of the sensor prism, the transmitter being configured to transmit the optical signal through the sensor prism to the rear end of the plunger, the receiver being configured to receive the optical signal reflected back from the plunger rear end and returned through the sensor prism.

In one embodiment, the face of the sensor prism on which the optical sensor is mounted is substantially orthogonal to the direction of travel of the plunger.

Also disclosed is a drug delivery device comprising a delivery unit comprising a drug container, a liquid flow system, a pressurized gas source, and a housing enclosing at least a portion of the drug container, the pressurized gas source, and the liquid flow system therein. The medicament container includes a barrel portion and a plunger slidably mounted within the barrel portion and sealing medicament within the container at one end of the barrel portion. The medicament container is received within a container receiving cavity of a container housing portion of the housing, the container receiving cavity being fluidly interconnected in a gas tight manner to a fluid outlet of the pressurized gas source. The pressurized gas source is configured to supply pressurized gas within the container receiving cavity to apply pressure at the rear end of the plunger for delivering the liquid medicament. The drug delivery device further comprises a pressure sensor fluidly coupled to the reservoir housing to measure the pressure within the reservoir housing, the pressure sensor being connected to an electronic control system configured to measure the pressure detected by the pressure sensor over time and to determine the position of the plunger over time based on the pressure measurements over time, including a stop of the plunger movement due to a blockage of the drug delivery flow system or an end of travel of the plunger within the reservoir (corresponding to a reservoir empty position).

In an advantageous embodiment, the pressurized gas source comprises a pumping system configured to pump gas into the container receiving cavity, thereby exerting pressure on the rear end of the plunger.

In an advantageous embodiment, the pumping system is configured to pump ambient air into the container receiving cavity, thereby exerting pressure on the rear end of the plunger.

Also disclosed is a drug delivery device comprising a delivery unit comprising a drug container in the form of a cartridge containing a liquid drug therein, a liquid flow system, a pumping system and a housing within which at least a part of the drug container, pumping system and liquid flow system are mounted. The medicament container comprises a septum sealing an end of the medicament container. The liquid flow system comprises an injection delivery system comprising an injection needle configured for injecting a drug in an actuated state of the drug delivery device, the liquid flow system further comprising a container fluid connection system comprising a septum needle mounted on a movable septum needle support, a spring pressing the septum needle support towards the septum of the drug container, and a blocking mechanism movable from a blocking position, in which the septum needle support is held in a retracted position in which the septum needle is not in contact with the septum, to an actuated position, in which the septum needle support is released and allowed to travel towards the drug container septum such that the septum needle pierces the septum under the force of the spring.

In an advantageous embodiment, the blocking mechanism comprises a rotatable support ring and a blocking finger extending from the support ring and being rotatably movable with the support ring from a position in which the blocking finger engages the septum needle support and holds it in the retracted position to an actuated position in which the blocking finger is disengaged from the septum needle support to allow it to travel to an actuated position in which the septum needle pierces the septum.

In an advantageous embodiment, the septum needle support comprises a flange portion and a gap between the flange portions, the blocking finger engaging the flange portion during a blocking position in which the septum needle support is retracted.

In an advantageous embodiment, the septum needle support comprises guides in opposite positions engaging complementary guide portions in the housing for slidably guiding the septum needle support from the retracted position to the septum piercing position.

In one advantageous embodiment, the injection delivery system comprises a needle actuation mechanism configured to move an injection needle from a retracted position within a housing of the drug delivery device to an extended delivery position in which the injection needle protrudes through a bottom wall of the housing, the needle actuation mechanism comprising a rotary actuation disc configured to engage an actuation lever coupled to the slidable septum needle support for transfer between the retracted and extended delivery positions.

In an advantageous embodiment, the actuation disc is directly coupled or integrally formed with the rotor of the pump engine of the pumping system.

In an advantageous embodiment, the actuating lever is coupled to the blocking mechanism to move it from the locked position to the unlocked position.

In an advantageous embodiment, the actuation rod comprises a support ring mounted around a shield portion of the housing surrounding a cavity in which the membrane end of the medicament container is accommodated.

In an advantageous embodiment, the actuation lever comprises a lever arm extending from the rotatable support ring, the lever arm being configured to engage a recess in the actuation disc upon initial actuation of the drug delivery device.

Also disclosed is a drug delivery device comprising a housing, a delivery unit comprising a drug container, and a control unit mounted within the housing, the control unit comprising an on-body sensing system comprising an electrode connected to an electronic control system of the control unit to measure a capacitance value, the electrode being configured to detect whether the drug delivery device is positioned against the skin of a patient. The skin contact wall of the housing has an inner side facing the interior of the housing in which the delivery unit and the control unit are mounted and an outer mounting side facing the exterior of the housing and intended to be placed against the skin of a patient. The electrode comprises a metal layer mounted directly against the inside of the skin contact wall.

In an advantageous embodiment, the metal layer of the electrode consists of a metal layer deposited directly on said inner surface of the skin contact wall.

In an advantageous embodiment, the directly deposited metal layer is an electroplated layer.

In an advantageous embodiment, the on-body sensing system further comprises a guard in the form of a conductor surrounding the electrode.

In an advantageous embodiment, the on-body sensing system is configured to measure a capacitance value between the electrode and a ground value.

In an advantageous embodiment, the on-body sensing system comprises a second electrode insulated from said electrodes constituting the first electrode, the potential between the first electrode and the second electrode being measured to determine the capacitance value.

In an advantageous embodiment, the second electrode is formed as a metal layer directly on the inner side of the mounting wall.

In an advantageous embodiment, the second electrode is formed as a metal layer in the same way as the first electrode.

In an advantageous embodiment, the second electrode and the first electrode have alternating portions.

In various embodiments, the drug container may include a septum at one end of the drug container that is perforated by a septum needle fluidly connected to the injection needle during actuation of the drug delivery device.

In various embodiments, the drug delivery device may comprise an injection needle mounted on a movable needle support configured to move the needle from its retracted position entirely within the housing to an actuated position in which the needle tip protrudes beyond the skin contact wall of the housing for injection delivery of the liquid drug.

In various embodiments, the liquid flow system may comprise an injection delivery system comprising an injection needle mounted on a movable needle support, the injection needle being connected via a catheter to a container fluid connection system comprising a septum needle.

In various embodiments, the drug delivery device may further comprise a drive unit comprising a pump driver having a coupling interface coupled to a drive coupling interface of a pumping system of the delivery unit, the pump driver providing torque to a rotor of the pumping system.

In various embodiments, the drug delivery device may comprise a housing within which the delivery unit and the drive unit are assembled, the housing comprising a skin contact wall for mounting against the skin of a patient, the skin contact wall comprising an adhesive patch with a protective film.

In various embodiments, for certain medical applications, the drug delivery device may be configured as a single-use disposable device, and in particular may be configured for single-dose administration of a liquid drug contained in a container.

Further objects and advantageous features of the invention will become apparent from the claims, detailed description and drawings, wherein:

drawings

FIG. 1a is a perspective view of a drug delivery device according to an embodiment of the present invention;

FIG. 1b is a perspective view of the device of FIG. 1a with the cover and adhesive with protective film exploded;

FIG. 2 is an exploded view of the embodiment of FIG. 1b with the cover and adhesive with protective film removed, showing the housing base, the transport unit and the drive unit;

FIG. 3a is an exploded view of the drive unit of FIG. 2 showing a medicament container within the drive delivery unit according to an embodiment of the present invention;

fig. 3b and 3c are perspective cut-away views of a transport unit according to an embodiment of the invention;

fig. 4a is a perspective view of a pump and a liquid flow system of a delivery unit of a drug delivery device according to an embodiment of the present invention;

FIGS. 4b and 4c are perspective exploded views of the liquid flow pumping system of FIG. 4 a;

FIGS. 5a to 5e are cross-sectional views of a liquid flow and pumping system of a drug delivery device according to an embodiment of the present invention, showing different steps of actuating a needle of a transdermal delivery system and a needle of a reservoir fluid connection system when actuating the drug delivery device;

FIG. 6a is a perspective view of the device of FIG. 5a in an initial position corresponding to FIG. 5a (with the outer housing portion removed to better view the interior);

FIG. 6b is a view similar to FIG. 6a, showing an intermediate actuated position corresponding to FIG. 5 c;

FIG. 6c is a view similar to FIG. 6b with a portion of the housing added in cross section, showing a position corresponding to FIG. 5e, which is the end position of full insertion of the two needles;

FIG. 6d is a perspective view of the device of FIG. 6a from the opposite side;

FIG. 6e is a view similar to FIG. 6d, showing an intermediate actuated position of the septum needle immediately before it is released;

FIG. 6e is a view similar to FIGS. 6d and 6f showing the end positions of the full insertion of the two needles;

FIG. 7a is a perspective cross-sectional view taken along line 7a-7a of FIG. 5 a;

FIG. 7b is a cross-sectional view taken along line 7b-7b of FIG. 5 e;

FIG. 8a is a cross-sectional view taken along line 8a-8a of FIG. 7 a;

FIG. 8b is a cross-sectional view taken along line 8b-8b of FIG. 7 a;

FIG. 9a is a cross-sectional view taken along line 9a-9a of FIG. 5 a;

FIG. 9b is a cross-sectional view taken along line 9b-9b of FIG. 5 e;

fig. 10a is a perspective exploded view of a drive unit of a drug delivery device according to an embodiment of the present invention.

Fig. 10b is a cross-sectional view of a part of a drug delivery device according to an embodiment of the present invention, showing the drive unit in an uncoupled state from the delivery unit of the drug delivery device according to an embodiment of the present invention;

FIG. 10c is a view similar to FIG. 10b, showing the coupled state;

FIG. 11a is a perspective view of a drug delivery device according to an embodiment of the present invention with a housing removed, showing an assembled delivery unit and drive unit, together schematically showing a plunger sensing system according to a first variant;

FIG. 11b is a cross-sectional view taken along line 11b-11b of FIG. 11 a;

FIG. 12a is a perspective view of a variation of the device of FIG. 11 a;

FIG. 12b is a cross-sectional view taken along line 12b-12b of FIG. 12 a;

FIG. 13 is a cross-sectional view of a liquid flow and pumping system of a drug delivery device showing an air flow system of a pneumatic drive according to an embodiment of the present invention;

FIG. 14a is a partial cross-sectional view showing a sealing membrane covering the pump engine coupling interface of the device of FIG. 13;

FIG. 14b is a perspective view of a first embodiment of a seal interface;

FIG. 14c is a perspective view of a second embodiment of a seal interface;

FIG. 15a is a schematic view of a drug container in a liquid flow pumping system of a drug delivery device showing a pneumatic driver and a pneumatic plunger sensing system according to an embodiment of the present invention;

FIG. 15b is a schematic illustration of a graph of pressure versus time for a pneumatic plunger system according to an embodiment of the present invention;

FIG. 15c is a schematic illustration of a graph of drug flow rate as measured by a pneumatic plunger sensing system over time according to an embodiment of the present invention;

FIG. 15d is a corresponding graph of air pressure in a container holder of a drug delivery device over time;

fig. 16a is a perspective view of a drug delivery device according to an embodiment of the present invention;

FIG. 16b is a perspective view of the drug delivery device of FIG. 16a with the drug container removed or prior to insertion into the drug delivery device;

FIG. 16c is a perspective view of a drug container for insertion into the drug delivery device of FIG. 16b and a closure cap mounted on a plunger of the drug container;

FIG. 16d is a cross-sectional view of the drug container cap of FIG. 16 c;

FIG. 16e is a cross-sectional view of the embodiment of FIG. 16 a;

FIG. 17a is a perspective partial cutaway view with certain components removed of a drug delivery device according to yet another embodiment of the present invention;

FIG. 17b is a view similar to FIG. 17a showing the components in a cross-sectional plan view;

FIG. 18a is a schematic view of an on-body sensing system of a drug delivery device according to an embodiment of the present invention;

fig. 18b is a perspective view of a delivery unit coupled to a drive unit of a drug delivery device, showing components of an on-body sensing system, according to an embodiment of the present invention;

FIG. 18c is a perspective view of a housing cover of the drug delivery device showing components of the on-body sensing system according to an embodiment of the present invention;

FIG. 18d is a schematic view of an on-body sensing system of a drug delivery device having two electrodes according to an embodiment of the present invention;

fig. 19a to 19d are schematic views of various embodiments of the assembly and sterilization steps of a drug delivery device according to various embodiments of the present invention.

Detailed Description

Referring to the drawings, a drug delivery device 1 according to an embodiment of the present invention comprises a housing 2, a delivery unit 3 and a control or drive unit 4, the delivery unit 3 and the control or drive unit 4 being assembled within the housing 2. The housing 2 may be made of two or more parts allowing the assembly of the transport unit, the drive unit and any other parts within the housing.

In the illustrated embodiment, the drug delivery device 1 is a single use disposable unit for subcutaneous administration of a liquid drug (medicament). Administration may be performed in a single dose in a short period of time (typically less than 1 hour, e.g., about 30 minutes or less). Single use disposable drug delivery devices may also be used to subcutaneously inject liquid drugs over a longer period of time from hours to days or even up to 1 to 3 weeks. Depending on the volume of drug to be injected, the drug delivery device may also be configured to inject liquid drug within a few minutes.

There are a number of applications in which it is advantageous to provide a drug delivery device to a patient in need of a drug, which may be worn on the patient's body, or which allows the patient to apply the device directly to his/her skin prior to use, to inject the drug outside a hospital or medical facility (e.g. at home). For certain medical applications, it may also be desirable to deliver liquid drugs for a period of time after an event (e.g., surgical intervention, or other form of treatment in a hospital or clinic), such as once the patient returns to home. There may also be applications where it is advantageous to provide a patient with a drug delivery device for injecting a medicament at a specific time (e.g. once a week or once a month or various other intervals depending on the drug and treatment) without the patient having to administer the drug by a healthcare professional in a clinical setting, e.g. to allow the patient to be treated at home.

Although the embodiments shown in the figures relate to single use disposable drug delivery devices, drug delivery devices having disposable portions that are assembled to reusable portions that contain a drive unit, electronics, and a power source may also be used within the scope of the invention described herein for various aspects. The delivery unit 3 may be mounted in a housing of the drug delivery device and the drive unit 4 may be mounted in a detachable housing part, so that the drive unit 4 may be reused with subsequent delivery units. Examples of drug delivery devices with single use disposable and reusable components are described for example in WO 2020109409.

The drug delivery device comprises a user interface 55, which user interface 55 may comprise one or more buttons, light and/or sound status indicators for actuating the drug delivery device and optionally a screen or other display for presenting information to an operator of the device.

Drug delivery devices according to embodiments of the present invention may advantageously be configured as patch devices for mounting on the skin of a patient. An adhesive layer (not shown) may be provided on the outer surface of the skin contact wall 81 of the housing 2 (e.g. on the surface of the cover 2 b) covered by a protective film that may be peeled off the adhesive layer prior to placement of the adhesive layer on the patient's skin injection site. The needle aperture 10 through the skin contact wall 81 is covered by a protective membrane 11 prior to use and allows the percutaneous injection needle 15 to extend therethrough and pierce the skin of a patient upon actuation of the drug delivery device 1.

The delivery unit 3 comprises a drug container 6 (e.g. a cartridge) containing a liquid drug 78, a liquid flow system 7 for guiding the liquid drug subcutaneously to the patient, a pumping system 8, and a housing 9 for accommodating the drug container, the liquid flow system 7 and the pumping system 8.

In an embodiment, the housing 9 may be configured to close the medicament container in an airtight manner such that air pressure may be generated within the housing portion around the medicament container for achieving a pumping action of the medicament, as will be described in more detail herein.

The medicament container 6 may be a conventional type cartridge comprising a container having a cylindrical portion 6a, a neck portion 6b having an open end closed by a septum 6c, and a plunger 12 closing the open end of the cylindrical portion 6a, a liquid medicament 78 to be administered to a patient being sealingly contained within the cylindrical portion 6a between the plunger and the septum. Such medicament containers 6 are well known in the pharmaceutical industry and may be used to contain many different types of liquid medicaments in a sterile manner. Such medicaments may also be provided in different sizes (volumes), it being understood that a medicament delivery device according to embodiments of the present invention may be sized to accommodate different types of medicament containers depending on the medical application. Embodiments of the present invention may also be used with non-standard drug containers.

While certain aspects of the invention disclosed herein require a drug container that includes a sliding plunger, it may be noted that certain other aspects of the invention disclosed herein are not limited to use with drug containers having a plunger, and may be used with other forms of drug containers without a plunger. For example, as will be further described, the on-body sensing system is independent of the type of drug container used in the drug delivery device. Also, for example, as will be further described, the container fluid connection system 17 requires a drug container with a pierceable sterile barrier, but does not necessarily require a drug container with a plunger. In addition, as will be further described, the method of producing the drug delivery device is independent of the type of drug container used in the drug delivery device.

The delivery unit 3 incorporates a pumping system 8, which pumping system 8 pumps liquid from the container to the injection needle 15 upon actuation of the drug delivery device. The pumping system comprises a drive coupling interface 33 coupled to a coupling interface 54 of a pump driver 52 of the drive unit 4. Thus, the drive unit provides mechanical power via the couplings 54, 33 to drive the pumping system 8.

Pump motor 28 may advantageously comprise a similar design and construction to the pump motor described in WO 2007074363 or WO 2015015379, wherein rotor 32 is mounted within stator 29 and is rotatably and axially movable within the stator to pump fluid from fluid inlet 30 to fluid outlet 31. As is known from the above publication, the rotor 32 has a pump shaft 36, the pump shaft 36 having a first diameter and a second diameter surrounded by a seal, the seal opening and closing a fluid passage between the inlet and the outlet when the stator is rotated and axially displaced due to a cam mechanism between the stator and the rotor, thereby performing a pumping action during opening and closing of a valve between the fluid inlet and the pumping chamber, between the pumping chamber and the outlet, respectively.

In summary, the pump engine 28 according to the preferred embodiment includes:

The stator 29 is provided with a stator,

a rotor 32 at least partially slidably and rotatably mounted in the stator, the rotor comprising a first axial extension having a first diameter and a second axial extension having a second diameter larger than the first diameter,

a first valve formed by a first valve seal mounted on the stator about a first axial extension in combination with a first passage in the rotor, the first passage configured to allow liquid communication across the first valve seal when the first valve is in an open position,

-a second valve formed by a second valve seal mounted on the stator about a second axial extension in combination with a second passage in the rotor, the second passage being configured to allow liquid communication across the second valve seal when the second valve is in the open position.

While the general design of pump engines and the principle of pumping action may be understood by reference to the above publications, in embodiments of the present invention the pumping system is not fluidly connected to the liquid to be administered. In contrast, in embodiments of the present invention, a pump motor may be advantageously used to pump air that creates pressure on the container plunger to move the plunger and force liquid out of the container when the septum is pierced.

In an advantageous embodiment of the invention, particularly for single use and single injection of the content of the drug container (e.g. over a period of several minutes to 60 minutes), the pump motor may be used to pump air which creates a pressure on the plunger 12 to push the plunger towards the membrane and the liquid 78 in the container through the injection needle 15 of the subcutaneous delivery system 13 via the liquid flow system 7. In these embodiments, the pumping system 8 thus acts as a pneumatic drive, creating air pressure within at least a portion of the housing 9 behind the plunger 12, as best shown in fig. 13.

In embodiments of the present drug delivery device, one important advantage of using such a pump motor is: there is no direct connection of fluid between the inlet and outlet at any position of the rotor and no actuation of any valve is required, so that a particularly reliable and leak-free pumping of gas is ensured in an easy-to-operate arrangement. The pump motor 28 is very compact and can be driven directly by the rotary motor 53 of the pump driver 52 in the drive unit 4 without transmission. Indeed, due to the differential pumping volume displacement defined by the axial displacement of the rotor and the difference between the first and second diameters of the pump shaft, the pumping volume displacement rotation can be easily configured to achieve optimal operation of a given type of motor with constant speed rotation. Furthermore, the pump motor components may be made entirely of polymeric material, and the rotor may be easily coupled to the pump driver, ensuring a sterile barrier between the fluid portion of the pump motor and the coupling interface.

It may be noted that certain aspects of the embodiments of the invention described herein do not necessarily rely on pneumatic drives to perform their function. For example, the on-body sensing system 5 and the plunger sensing system 70 using the optical sensor 71 do not necessarily require a pneumatic driver and may also be implemented in a drug delivery device, wherein the pump motor acts directly on the liquid drug in a conventional manner or using other pump systems known per se for directly withdrawing liquid from a container (e.g. as described in WO 2015015379). Moreover, the reservoir fluid connection system 17 (described in more detail below) may also be implemented with different pumping systems, such as a pneumatic drive, or a drive which is mechanically pressed against a plunger, known per se, or by using the motor described in WO 2015015379 to extract the liquid.

The drive unit 4 is mainly configured to drive the pumping system 8 of the delivery unit 3, but may also have additional functions, such as processing the sensing signals and sending and receiving data from external devices via a wireless communication link (e.g. using bluetooth).

The drive unit 4 comprises an electronic control system 47, which electronic control system 47 may comprise a circuit board 48, on which circuit board 48 electronic components comprising at least one microprocessor 49 and optionally a wireless connection module are mounted. The electronic control system further comprises a power source 50, for example in the form of a battery, and a pump driver 52 comprising an electric motor 53.

The axis of the motor 53 may be coupled to a coupling interface 54, which coupling interface 54 is configured to engage a complementary coupling interface 33 of the pump motor rotor 32 on the delivery unit 3. If pump motor 28 is configured with a rotatable and axially movable rotor as discussed above, in a preferred embodiment, drive coupling interface 54 is axially slidable relative to the motor output shaft and biased by spring 69, spring 69 presses motor drive coupling interface 54 against coupling interface 33 of pump motor rotor 32, as best shown in fig. 10 a-10 c.

The drive unit may further comprise a plunger sensing system 70 for sensing the position of the container plunger. The plunger sensing system is used to determine the correct operation of the drug delivery device and to identify for example a blockage in the liquid flow system or to identify the end of the stroke of the plunger when the drug container is empty at the end of a drug administration process. Embodiments of the plunger sensing system 70 will be described in further detail.

It may be noted that the plunger sensing system 70 for sensing plunger position according to embodiments of the present invention may be implemented on a variety of drug delivery systems having a drug container comprising a plunger, such as on a syringe device, an automatic injector, a pen injection system (like an insulin pen), or any other plunger movement of a primary package of liquid medicament.

The drive unit may further comprise an on-body sensing system 5 for detecting whether the drug delivery device is positioned against the skin of the patient. If the drug delivery device is not positioned against the patient's skin, the on-body sensing system may prevent operation of the drug delivery device and may also detect if the drug delivery device is removed before the drug is completely delivered. Embodiments of the on-body sensing system 5 will be further described in more detail.

The liquid flow system 7 comprises a subcutaneous delivery system 13 and a container fluid connection system 17, the subcutaneous delivery system 13 comprising an injection needle 15 for piercing the skin of the patient, the container fluid connection system 17 comprising a septum needle 18 for piercing the septum 6c of the container 6 upon actuation of the drug delivery device. The subcutaneous delivery system comprises a needle support 16 slidably mounted within the housing 2 along a housing slide 67, the needle being mounted on the needle support and movable together with the needle support 16 from a fully retracted position within the housing 9 of the delivery unit 3 (as shown in fig. 6a, 6d and 9 a) to a fully extended position during administration of the medicament (as shown in fig. 6c, 6f and 9 b).

The needle and the fluid channel in the needle support are connected to a catheter 14, which catheter 14 may advantageously be in the form of a flexible tube allowing the needle support to be slidingly moved from a retracted position to an extended position, which tube is connected at its other end to a container fluid connection system 17.

The container fluid connection system 17 includes a septum needle support 19, the septum needle 18 being mounted on the septum needle support 19, the septum needle support 19 being slidably mounted within the housing configured to move from a retracted position as shown in fig. 6a, 6d, 7a and 8a to an extended position as shown in fig. 6c, 6f, 7b and 8 b. In the retracted position, the septum needle 18 is not in contact with the medicament 78 in the medicament container, and in the extended position, the septum needle has pierced the sealing member 27 (sterile barrier) and septum 6c of the medicament container and is in contact with the liquid 78 in the container.

In an advantageous embodiment, the reservoir fluid connection system 17 may be actuated simultaneously with the subcutaneous delivery system 13. It may be noted, however, that it is within the scope of the present invention to actuate the reservoir fluid connection system 17 prior to actuating the subcutaneous delivery system 13, for example, in a sequential manner. The step of first fluidly connecting septum needle 18 to the drug prior to piercing the skin of the patient with injection needle 15 may allow the fluid connection comprising catheter 14 to be filled with the drug prior to injection in order to remove air in the fluid channel prior to injection.

In an advantageous embodiment, the container fluid system 17 comprises a slidable needle support 19 having a flange portion 20, the flange portion 20 having a guide 22 at an outer end, the guide 22 slidably engaging in a complementary guide in the housing portion of the housing 9. The container fluid connection system 17 further includes a blocking mechanism 24 having blocking fingers 26. In the locked position, in which the septum needle support 19 is in the retracted position as shown in figures 6a, 6d, 7a and 8a, the blocking finger 26 blocks the septum needle support in the retracted position by pressing against the at least one flange portion 20. The spring 23, which may for example be in the form of a conical helical spring, is pressed against the rear side of the septum needle support with a spring force configured to move the septum needle support towards the drug container and through the sealing member 27 (sterile barrier) and the septum 6 c. Other forms of springs may be provided within the scope of the invention. The blocking finger 26 may be moved out of engagement with the septum needle support, for example by being moved in a gap between the flange portions 20, such that the spring 23 pushes the septum needle support towards the sealing member 27 and the septum 6c such that the septum needle 18 pierces the sealing member and the septum.

In an advantageous embodiment, the blocking mechanism 24 may comprise a rotatable support ring 25, from which rotatable support ring 25 blocking fingers 26 protrude. A rotatable support ring 25 is for example mounted around a shroud forming a cavity into which a container lid with a membrane 6c is inserted.

The blocking mechanism may be actuated to release the septum needle support allowing it to travel from the retracted position to the extended position by rotation of the blocking mechanism 24.

In an advantageous embodiment, the movement of the blocking finger 26 and its release from the septum needle support 19 may be performed by actuation of a pump motor 28 of the pumping system 8. Subcutaneous delivery system 13 may also be simultaneously actuated by initial rotation of rotor 32 of pump motor 28.

In the present invention, the subcutaneous delivery system may comprise a similar construction to the delivery system described in WO 2015015379, which is incorporated herein by reference. In this configuration, the rotor 32 of the pump engine 28 includes an actuation disc 34 coupled to the pump shaft 36 that includes a notch 35, the notch 35 engaging the tip of a lever arm 65 connected to a support ring 66 of an actuation lever 64. As best shown with reference to fig. 5a to 6c and fig. 4b and 4c, the support ring 66 of the actuation lever 64 is rotatably mounted around a shroud forming a cavity accommodating the container lid, while the lever arm 65 extends to a tip configured to catch in the recess 35 of the actuation disc 34 when the rotor 32 is rotated by the pump driver 52 of the drive unit 4.

As shown in fig. 5a and 6a, an initial position is shown prior to first use of the drug delivery device, wherein the tip of the lever arm 65 abuts against the outer circumferential surface of the actuation disc 34. The pumping operation starts when the drug delivery device is actuated, at which time the actuation disc 34 is rotated (in the counter clockwise direction in the drawing) such that the tip of the lever arm 65 engages in the recess 35, as best shown in fig. 5 b. Subsequently, continued rotation of the rotor causes the actuation lever 64 to pivot (in a clockwise manner in the figures, as shown in fig. 5c, 5d and 6 b) until the fully actuated position shown in fig. 5e, in which the needle 15 is fully extended. The actuating lever 64 is also coupled to the support ring 25 of the blocking mechanism 24 by a pin, protrusion or other mechanism (not visible in the figures) and rotates it (in a clockwise manner as shown in fig. 5b to 5 d) such that its blocking finger 26 disengages from the septum needle support 19.

Thus, in the above-described advantageous embodiments, actuation of the pump driver automatically and simultaneously actuates the subcutaneous delivery system 13 and the reservoir fluid connection system 17 to administer the medicament. The advantage of such simultaneous actuation upon actuation of the pumping system is that it ensures that the medicament is sealingly contained within the container until the medicament is administered to the patient, thereby improving sterility and shelf life.

As best seen in fig. 7a and 3c, a sealing member 27 may be provided to cover the central aperture in front of the retracted septum needle 18 before the septum needle pierces the container septum.

The aperture 68 (see fig. 9a, 9 b) in the housing 9 through which the injection needle 15 extends may also comprise a sealing member that is pierced during actuation of the injection needle.

At the end of the injection cycle, the rotor 32 of the pump motor 28 may be reversed to pivot the actuating lever 64 and lever arm 65 in opposite directions to move the needle support 16 back up to retract the injection needle 15 within the housing 9. The patient can then safely remove the drug delivery device without any risk of any person being pricked by the injection needle 15.

In a variant (not shown), actuation of the container fluid connection system may be performed by a different mechanism, such as a manually actuated button on the housing, pressing the blocking finger 26 out of engagement with the septum needle support 19. In this configuration, sensors may be provided to prevent actuation of the subcutaneous delivery system 13 and the pumping system 8 until the container fluid connection system 17 has been actuated.

In embodiments comprising a pneumatic drive, the housing 9 comprises a container housing 38, the container housing 38 having a container receiving cavity 75 therein, the container receiving cavity 75 surrounding the medicament container 6 and being sealingly connected to a portion of the pump and needle system housing 37 surrounding the septum needle outlet aperture. The interior of the reservoir housing 38 is fluidly connected to the outlet 31 of the pump motor 28 via a fluid passage 74, as best shown in fig. 13. The pneumatic flow system 74 is isolated from the volume within the pump and needle system housing 37 around the pump motor 8 within which the inlet 30 on the stator 29 of the pump motor 28 is positioned to draw air into the pump motor. Thus, the housing 9 may be provided with a valve inlet or a filter inlet (not shown) to allow air to be drawn into the volume surrounding the pump engine.

Advantageously, in the pneumatic driver configuration of the present embodiment, the pumping system 8 is actuated to generate a gas pressure within the reservoir housing 38, which thereby exerts a pressure on the rear end 73 of the plunger 12. This configuration allows a very compact delivery unit and thus a very compact drug delivery device 1, since only very little space is required behind the plunger as there is no mechanical driver pushing the plunger directly. Moreover, the use of a pump motor 28 as described above, which is known per se for pumping liquids, is particularly advantageous in pneumatic drive applications, in view of the very compact dimensions and the ability to pump gas without the need for additional valves. Furthermore, the pump may be driven by an electric motor without the need for a transmission. Sterilization of the delivery unit 3 is also easily performed with gamma radiation as a substantially closed unit prior to assembly with the medicament container 6.

Referring to fig. 15a to 15d, a drug delivery device with a pneumatic flow system and a pneumatic drive may comprise a pressure sensor 80 measuring the pressure in the pneumatic flow system 71. As shown in fig. 15b, the pressure in the pneumatic flow system measured over time is indicative of the displacement of the plunger 12. The blockage of the plunger due to blockage in the liquid flow system can be detected by an increase in the rate of increase of pressure over time. Moreover, the end of the stroke of the plunger, i.e. the emptying of the medicament container, can also be easily detected, e.g. by an increase in the rate of pressure increase identified in part E of fig. 15 b.

As shown in fig. 15b, if a pneumatic pump system as described above is used, the air pumping action is preferably transferred in a pulsed manner, whereby there is a pumping phase followed by a non-operating phase in which the pump is stopped so that there is a change in air pressure, creating a saw tooth feature as shown in fig. 15b and 15 d. Each active pumping phase may be obtained by a single rotation period (360 ° rotation) of the pump motor rotor 32 or by a predefined plurality of rotation periods. The non-operational phase in which the pump is stopped may be of a predetermined duration, depending on the desired drug delivery rate.

The pressure sensor is very economical and easy to integrate. Thus, the advantages of this pneumatic plunger position sensing system are that it is very low cost and easy to integrate, and it is particularly suitable for a single injection cycle where it is required to control the average flow rate (e.g. as shown in fig. 15 c) and the final position of the plunger in the container should be determined. In this case, there is no need to precisely verify the position of the plunger.

The plunger position may also be determined by other sensing means and in another embodiment the plunger sensing system 70 comprises an optical sensor 71 mounted on the rear end of the container facing the end 73 of the plunger 12. The container housing portion 38 of the housing 9 includes a sensor window 43 or sensor prism 43' mounted on the end 42 of the container housing 38 facing the plunger 12.

The optical sensor 71 may be positioned on an outer surface of the sensor window 43 or the sensor prism 43', the sensor window 43 or the sensor prism 43' being made of a transparent material for the optical signal of the optical sensor 71. The optical sensor system may advantageously comprise an emitter 71a and a receiver 71b, the distance of the sensor window to the plunger rear end 73 being measured by time of flight (TOF) measurements. Advantageously, such a time-of-flight optical sensor is particularly economical and easy to implement. To obtain practical measurements, a window 43 may be positioned on the protruding plunger end 42 to have some minimum distance from 3mm up to 30mm (e.g., between 5 and 20 millimeters) in the initial position of the plunger 12 when the container is full, so that the plunger initial position can be more easily detected by optical time-of-flight measurements.

The optical sensor 71 may be mounted on a circuit substrate 72 protruding laterally from the drive unit 4, as schematically shown in fig. 11a, 11b and 12a, 12 b. In the variant shown in fig. 12a, 12b, the optical sensor may be positioned such that the light is directed orthogonally to the direction of travel of the plunger, the light being reflected via a prism 43', the prism 43' having an internal reflecting surface for total internal reflection, as is known per se in the optical field. The prism also has the effect of increasing the initial travel of the transmitted and reflected light so that a meaningful measurement of the initial position of the plunger can be made when the container is full.

The accuracy of the time-of-flight measurement increases as the plunger moves toward the container empty position, so that greater accuracy can be obtained when the container reaches the empty position.

The optical sensor may be used with a pneumatic drive as described previously, but may also be used in a drug delivery system with other pumping techniques, such as using a pump motor that directly draws liquid from a drug container and displaces the plunger 12 within the container by aspiration (reduced pressure).

Thus, the plunger sensing system 70 having the transparent window-based optical sensor 71 at the rear end of the container housing 38 is particularly cost-effective and easy to deploy in a very compact arrangement.

Referring to fig. 16a to 16e, another embodiment of a drug delivery device 1 is shown, having a different arrangement of housings 2. In this embodiment, rather than providing a container housing 38 extending the entire length of the container 6, a cap 44 is provided, forming a plunger end 42 of the container housing configured to close a container receiving cavity 75 within the housing 2. A sealing ring 41 may be provided between the lid and the cavity wall to sealingly close the container 6 within the housing 2. The optical sensor 71 of the plunger sensing system 70 may be incorporated within the cap 44, which is also positioned on the transparent sensor window 43. The optical sensor 71 may be mounted on a circuit substrate 72, which circuit substrate 72 is electrically interconnected to the contacts 45, the contacts 45 protruding from the outer surface of the cover for electrical connection with complementary contacts 45 on the housing 2. In this embodiment, the container 6 may thus be mounted within the housing after assembly of the drive unit 4 and the delivery unit 3, for example for allowing insertion of the container 6 by a patient or healthcare practitioner, rather than factory mounting.

Referring to fig. 17a and 17b, a further embodiment of the drug delivery device is disclosed, which, like the embodiment of fig. 16a to 16d, also allows for insertion of the drug container 6 by a healthcare practitioner or user after assembly of the housing, drive unit and delivery unit at the factory. In this embodiment, the rear open end of the container housing 38 is closed by a lid 2c, the lid 2c being hingedly coupled to the base 2a of the outer shell 2 via a hinge coupling 46 and comprising a container sealing ring 77, which container sealing ring 77 is inserted and hermetically seals the rear open end of the container housing part 38 once the container is inserted therein. It may be noted that in fig. 17a and 17b, parts of the drive unit are not shown to increase the clarity of the illustration of the other components.

Referring now to fig. 18a to 18d, a drug delivery device according to an embodiment of the present invention advantageously comprises an on-body sensing system 5 electrically connected to an electronic control system 47 of the drive unit 4. The on-body sensing system 5 is based on capacitance measurements that detect the presence of body tissue in the vicinity of the capacitive sensor. Capacitive sensors for measuring the proximity of a medical device on the sensor skin are known per se, whereas conventional sensors are either not particularly reliable or are costly to integrate in a drug delivery device. In the present invention, the on-body sensing system 5 comprises an electrode 56, which electrode 56 comprises a metal layer formed directly on the inner surface of the contact wall 81 of the housing, the outer surface of the skin contact wall 81 of the housing being configured to be placed against the skin of the patient.

The electrode 56 may advantageously be formed by depositing a metal layer (e.g., an electroplating process) on the inner surface of the housing cover 56. The electroplating process may be a galvanic electroplating process, but other metal deposition techniques for forming a metallization layer directly on the inner surface of the skin contact wall 81 may be utilized within the scope of the present invention. The housing may be made of a thermoplastic or thermosetting polymer and is thus an insulating material. The electrodes 56 may be connected to the electronic control system 47 of the drive unit 4 via interconnection terminals 61.

The interconnect terminals 61 may be connected to the circuit board 48 of the electronic control system 47 at circuit board connection ends 62 (e.g., by soldering to circuit traces on the circuit board) and extend to electrode connection ends 63 that contact the metal electrode layer 56. The electrode connection end 63 may be resiliently supported, for example by being provided at an end of a spring beam configured to press against the metal layer of the electrode 56 when the drive unit 4 is assembled within the housing 2.

An electronic component, such as a microprocessor 49 of the electronic control system 47, may be connected to the electrodes to measure the capacitance value and the change in capacitance value for detecting when the drug delivery device is placed against the skin of the patient.

Activation of the drug delivery device may be configured in the electronic control system 47 to be possible only if the on-body sensing system detects the correct position of the drug delivery device on the patient's skin.

In a first embodiment, the on-body sensing system comprises a sensor electrode implemented as a single electrode, wherein the capacitance between the electrode and the reference potential is measured.

In the second embodiment, the sensor electrode may also be implemented as a pair of electrodes 56a, 56b, in which the capacitance therebetween is measured. This has the advantage that false detections due to external factors affecting the capacitance measurement, such as the moisture (sweat) of the contact interface, which the measurement system may reject, can be reduced.

The metal layer on the inner surface of the housing 2 is also advantageous in that a large surface area can be covered by the electrodes for reliably reading varying capacitance values taking into account a large capacitive coupling with the patient's skin.

In a variant, the on-body sensing system may further comprise a conductive guard frame 57 surrounding the electrodes, which provides some protection against interference from external fields. The shield may also be connected to the circuit board 48 of the electronic control system by contacts similar to those described above for connection to the electrode layers. Instead of using a metal layer deposited directly on the inner surface of the housing wall mounted against the skin of the patient, the electrode may also comprise a stamped metal sheet or foil of conductive material bonded or secured directly against the inner surface of the housing instead of the deposited metal layer. The conductive foil may be bonded to the inner surface of the housing wall 81, for example by adhesive or welding, so as to form a stable electrode.

With reference to fig. 19a to 19d, an advantageous method of assembling a drug delivery device according to an embodiment of the present invention is described. Referring first to fig. 19a, the production of components of a drug delivery device which have to be sterilized in a highly reliable manner is disclosed. As shown, a single component for a fluid package is manufactured and assembled, which corresponds to the liquid flow system 7 and pumping system 8 in the housing 9 of the above-described embodiment. The container housing shown in fig. 19a corresponds to the container housing 38 and is assembled to the other housing parts once the medicament container 6 has been inserted therein. The medicament container parts are manufactured separately and the medicament container is assembled to the fluid package in the container housing under sterile conditions (according to ISO standard 5 in the present example). Both the container housing and the fluid package, i.e. the liquid flow system 7, the pumping system 8 and the housing 9, can be sterilized with gamma sterilization, which is very reliable for killing all pathogens. Other sterilization methods may be employed within the scope of the present invention, including chemical and thermal sterilization methods, including NO2 (nitrogen dioxide), VHP (vaporized hydrogen peroxide), ETO (ethylene oxide), and steam sterilization methods. The container packet formed by the assembly of these components thus corresponds to a delivery unit 3 containing all the components that requires a very high degree of sterilization.

As noted in relation to the previously described embodiments, all outlets of the delivery unit 3 are provided with seals, in particular a sealing membrane 27 covering the container fluid connection system 17, a sealing ring 41 between the container housing 38 and the pump and needle housing 37, and a seal 79 covering the interface between the pumping system rotor and the drive coupling interface 33. The sealing membrane 79 may completely cover the drive coupling interface 33 (as shown in fig. 14 c), or may cover only the gap between the rotor and the stator. The sealing membrane 79 may be interface bonded or welded to form an airtight seal, and may be frangible, for example, such that when the drive unit is assembled to the delivery unit and when the device is actuated in use, the seal breaks or ruptures. Thus, the delivery unit remains sterile and has a long shelf life until the drug delivery device is used.

The production of the fluid package, container lid and medicament container may be performed in a single manufacturing facility and assembled in the same manufacturing facility as shown in fig. 19 a.

In a variant, as shown in fig. 19b, the fluid cap and the container cap may be manufactured in a first manufacturing facility and preferably sterilized using gamma sterilization as in the method according to fig. 19a, and subsequently supplied to a second facility, e.g. located in a pharmaceutical company, where the drug container is manufactured and filled. As mentioned above, other sterilization methods may be employed within the scope of the present invention, including chemical and thermal sterilization methods (e.g., NO2, VHP, ETO, and steam sterilization methods). Thus, the assembly of the drug container and the fluid package and the container lid for forming the delivery unit 3 may be formed in a second manufacturing site where the container package is produced.

As shown in fig. 19c and 19d, the sterile container package representing the delivery unit 3 in the embodiments herein may then be assembled to electronics (representing the drive unit 4 in the embodiments herein) and optionally other non-sterile components to finally assemble the drug delivery device under controlled conditions, e.g. ISO 9 standard.

As shown in fig. 19d, various configurations of manufacturing and assembly may be performed at different locations. For example, the drug container component may be supplied to a drug manufacturer performing a filling process, and the fluid package and the container cap may be supplied to a pharmaceutical company at a second location for assembling the container to the fluid package and the container cap to form a cartridge package (i.e. corresponding to the delivery unit 3 of the embodiments described herein). The cartridge package may then also be assembled to the electronic components (i.e. corresponding to the drive unit 4 for the embodiments described herein) and other components to the cartridge package within the pharmaceutical company site to form the drug delivery device.

Advantageously, the configuration of the delivery unit with the housing 9 containing the liquid flow system 7 and the pumping system 8 may be sterilized with gamma sterilization, then assembled to the drug container 6 to form a sealed sterile delivery unit, which may then be assembled to non-sterile components (e.g. electronics of the drive unit 4 and the housing component 2). The assembly process provides an efficient manufacturing process, while also ensuring sterility and safety of the drug delivery device when needed.

In summary, a method of producing a drug delivery device, comprising:

-a control unit comprising electronic components, and

the outer shell is a shell with a hollow,

according to an embodiment of the invention, the method comprises the following steps:

a) Assembling the components of the fluid package to form the fluid package,

b) The fluid-bag is subjected to a sterilization process,

e) Assembling the fluid package to a pre-filled drug container to form a container package system,

f) Assembling the container package system to the control unit and the housing (2) to form a drug delivery device,

wherein steps c) and e) are performed under aseptic conditions.

In an advantageous embodiment, the medicament container comprises a cylindrical portion and a plunger slidably mounted within the cylindrical portion and sealing the medicament within the container.

Step a) involves the assembly of a fluid pack of the drug delivery device. The fluid package comprises at least a liquid flow system capable of providing a fluid connection from the pre-filled drug container to the patient's body during a drug delivery action of the drug delivery device. Fluid flow systems are typically composed of different components of different materials. For example, the patient side cannula is composed of metal, while the fluid path is typically composed of a hose or channel made or formed of plastic parts.

Step b) involves sterilization of the fluid packet. Since the assembled fluid package is not typically manufactured under aseptic conditions, the fluid package must be sterilized to ensure that the patient cannula, barrel needle and overall fluid path are not contaminated. The usual sterilization methods to achieve sterility of the assembly depend on the combination of different materials and the product design (e.g. grooves). Methods of sterilization for the fluid Bao Chang are gamma radiation, ethylene oxide (ETO) sterilization, nitrogen dioxide (NO 2) sterilization, steam sterilization, vaporized Hydrogen Peroxide (VHP) sterilization, X-ray sterilization, or electron beam sterilization.

Step c) involves providing a prefilled drug container. The container may be made of glass, polymer or other material that is inert to drug stability and preferably biocompatible. Glass is commonly used in FDA approved commercial drug containers produced by many different manufacturers. Thus, aseptic filling and storage of medications in glass containers has been a well established, approved procedure that can expedite the approval process of a drug pump device that protects the medication in the glass container. Polymeric containers, for example made of COP (cyclic olefin polymer) or COC (cyclic olefin copolymer), may be suitable for certain drugs, such as protein drugs, which degrade faster when in contact with glass. After filling, the container is closed with a plunger, typically made of a rubber material. Such containers are filled and closed under aseptic conditions (5 or lower orders as specified in ISO 14644-1).

Step d) involves assembling the fluid pack to the pre-filled drug container to form a container pack system, which may have a fluid connection between the fluid pack and the pre-filled drug container, or may establish the connection separately, e.g. after production or immediately prior to delivering the drug to the patient.

Step e) involves assembling the container package system to the control unit and the housing (2) to form the drug delivery device. The assembly of the control unit with the user interface of the container package system and the mounting of the housing may be accomplished by standard form-fitting connections or any other conventional manufacturing method. This may also include welding or gluing processes in order to achieve a watertight or even airtight housing.

Definition of aseptic conditions: in addition to low particle counts, aseptic conditions ensure that the filling and assembly environment is free of pathogens, such as bacteria, viruses and other pathogenic microorganisms.

Sterile conditions may be achieved in, for example, class 5 clean rooms or lower (i.e., higher standard clean rooms) as specified in ISO 14644-1.

Another definition of aseptic conditions can also be found in the United States Pharmacopeia (USP) chapter <1116>, "microbiological control and monitoring of aseptic processing environments".

Another definition of sterility conditions can be found in "DIN EN ISO 13408-1, part 1: general requirements "are found in the following.

In an advantageous embodiment of the method, the container-packaging system comprises a container housing enclosing the prefilled drug container. The reservoir housing may be connected to a fluid bag so that the sterile condition of the prefilled drug container may be easily maintained. The container may be in direct fluid communication with the liquid flow system or the fluid package may include means for connecting the prefilled drug container to the liquid flow system separately (e.g., after manufacture or immediately prior to delivery of the drug to the patient).

In an advantageous embodiment of the method, the container-packaging system comprises a pump system. The pump system is configured to push the plunger further into the pre-filled drug container in order to administer the drug. In an advantageous embodiment, the pump system performs drug delivery by drawing ambient air and injecting it into the reservoir housing.

In an advantageous embodiment of the method, the pump system comprises a coupling interface of the pump system of the delivery unit, the pump driver providing torque to a rotor of the pump system, wherein the coupling interface is sealed by the sealing membrane to maintain sterility after step b). The seal may be made of a two-component molded thermoplastic elastomer (TPE) or a separate TPE or elastomer that seals against the moving coupling interface. The seal may also be made to completely cover the coupling interface and be broken when the coupling is first rotated. In this case, it may be made of a polyethylene foil (e.g. Tyvek ^TM Foil) instead of an elastic material.

Feature list

Medicament 78

Drug delivery device 1

Shell 2

Base 2a

Cover 2b

Skin contact wall 81

Pinhole 10

Adhesive layer

Protective film 11

Cover 2c

Container sealing ring 77

Hinge coupling 46

Conveying unit 3

Medicine container 6

Cylindrical portion 6a

Neck portion 6b

Diaphragm 6c

Plunger 12

Plunger rear end 73

Liquid flow system 7

Subcutaneous delivery system 13

Catheter 14

Injection needle 15

Needle support (slidable) 16 housing slide 67

Container fluid connection system 17

Septum needle 18

Septum needle support 19

Flange portion 20

Gap/cavity (for blocking finger release) 21 guide 22

Spring 23

Conical spring

Blocking mechanism 24

Support ring (rotatable) 25

Blocking finger 26

Sealing film 27

Actuating lever 64

Support ring 66

Lever arm 65

Pumping system 8

Pump engine 28

Stator 29

Fluid inlet 30

Fluid outlet 31

Rotor 32

Drive coupling interface 33

Actuating disk 34

Recess 35

Pump shaft 36

Sealing element

Pneumatic flow system 74

Housing 9

Pump and needle System housing 37

Needle outlet hole 68

Container housing 38

Container receiving chamber 75

Tubular portion 39

Diaphragm end 40

Sealing ring 41

Plunger end 42

Sensor window 43

Sensor prism 43'

Cover 44

The electrical contact interface 45 controls the unit or drive unit 4

Electronic control system 47

Circuit board 48

Microprocessor 49

Wireless connection module

Power supply (battery) 50

Pump driver 52

Electric motor 53

Coupling interface 54

Spring 69

User interface 55

Plunger sensing system 70

Circuit board 72

Optical sensor 71

Emitter 71

Receiver 71b

Prism 43', window 43

Electrical contact interface 45

On-body sensing system 5

Electrode 56

Metallization layer

Guard 57

Processing circuit 58

Circuit board 59

Microprocessor 60

Interconnection terminal 61

Circuit board connection end 62

Electrode connection terminal 63

Spring beam

Claims

1. Method for producing a drug delivery device comprising

A prefilled drug container (6),

a fluid package comprising a liquid flow system (7) providing a fluid connection from the drug container to the patient during a drug delivery action of the drug delivery device,

a drive unit comprising electronics and a pump driver (52),

-a housing (2),

the method comprises the following steps:

a) Assembling the components of the fluid package to form the fluid package,

b) The fluid-bag is subjected to a sterilization process,

e) Assembling the container package system to the drive unit and the housing (2) to form a drug delivery device,

Characterized in that the fluid package comprises a container housing (9) for receiving a pre-filled drug container (6) therein, and a pump motor (28) having a rotor (32) comprising a coupling interface (33) adapted to be coupled to a pump driver (52) for providing torque to the rotor, wherein the coupling interface is sealed by a sealing membrane (79) to remain sterile after step b), and

steps c) and d) are carried out under aseptic conditions.

2. The method according to the preceding claim, wherein step e) is not performed under aseptic conditions.

3. The method of any of the preceding claims, wherein the medicament container comprises a cylindrical portion (6 a) and a plunger (12) slidably mounted within the cylindrical portion and sealing medicament (78) within the container.

4. The method according to any of the preceding claims, wherein the sealing film may be made of a two-component molded thermoplastic elastomer (TPE) together with the housing or as a separately assembled part.

5. The method according to any of the preceding claims, wherein the sealing film is made of a polyethylene foil covering over the coupling interface.

6. The method of any one of the preceding claims, wherein the sealing membrane is configured to rupture upon actuation of the pump driver.

7. The method of any of the preceding claims, wherein the housing comprises a user interface (55).

8. The method according to any of the preceding claims, wherein the sterilization method of b) is any of gamma radiation, ETO sterilization, NO2 sterilization, steam sterilization, VHP sterilization, X-ray sterilization or electron beam sterilization.

9. The method according to any of the preceding claims, wherein the assembling step of step d) comprises a form-fitting connection.

10. The method of the preceding claim, wherein the form-fit connection provides an airtight seal of the prefilled drug container within the container package system.

11. The method of any one of the preceding claims, wherein the drug delivery device:

a delivery unit (3) comprising a drug container (6), a liquid flow system (7), a pumping system (8) comprising a pump driver (28), and a housing (9) enclosing the drug container, the pumping system and the liquid flow system therein,

-a drive unit (4);

and a housing (2) in which the conveying unit and the drive unit are mounted,

wherein the delivery unit in which the drug container is not assembled forms the fluid pack and wherein the delivery unit in which the drug container is assembled forms the container pack, and wherein the drive unit comprises an electronic control system (47) and a power supply (50).

12. The method of the preceding claim, wherein the medicament container is housed within a container receiving cavity (75) of a container housing portion (38) of the housing (9), the container receiving cavity being fluidly interconnected in an airtight manner to a fluid outlet (31) of a pumping system (8) comprising a fluid inlet (30) connected to ambient air, the pumping system being configured to pump ambient air inhaled through the fluid inlet (30) into the container receiving cavity (75) thereby exerting pressure on a rear end (73) of the plunger to deliver the liquid medicament.

13. Method according to any of the two preceding claims, wherein the liquid flow system (7) of the delivery system (3) comprises a container fluid connection system (17) comprising a septum needle (18) mounted on a movable septum needle support (19), a spring (23) pressing the septum needle support towards the septum of the drug container, and a blocking mechanism (24) movable from a blocking position, in which the septum needle support (19) is held in a retracted position, in which the septum needle (18) is not in contact with the septum (6 c) and behind the sterile barrier sealing member (27) of the housing (9), and in which the septum needle support is released and allowed to travel towards the drug container septum, such that the septum needle (18) pierces the sterile barrier sealing member (27) and the septum (6 c) under the force of the spring (23).

14. A method according to any of the three preceding claims in relation to claim 3, wherein the control unit comprises an electronic control system (47) and a plunger sensing system (70) comprising an optical sensor (71) comprising a transmitter (71 a) configured to transmit an optical signal to a rear end (73) of the plunger (12) and a receiver (71 b) configured to receive an optical signal reflected back from the plunger rear end (73), the plunger sensing system being connected to the electronic control system (47) configured to measure the time of flight of the optical signal from the transmitter to the receiver and thereby determine the position of the plunger within the cylindrical portion of the medicament container.

15. The method according to any of the four preceding claims, wherein the control unit comprises an on-body sensing system (5), the on-body sensing system (5) comprising an electrode (56) for measuring a capacitance value connected to an electronic control system (47) of the control unit, configured to detect whether the drug delivery device is positioned against the skin of the patient, the skin contact wall (81) of the housing (2) having an inner side facing the interior of the housing in which the delivery unit and the control unit are mounted and an outer mounting side facing the exterior of the housing and intended to be placed against the skin of the patient, wherein the electrode (56) comprises a metal layer mounted directly against the inner side of the skin contact wall.